Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance

• Published in: Cell metabolism 2020-09, Vol.32 (3), p.391-403.e6
• Main Authors: van Gastel, Nick, Spinelli, Jessica B., Sharda, Azeem, Schajnovitz, Amir, Baryawno, Ninib, Rhee, Catherine, Oki, Toshihiko, Grace, Eliane, Soled, Heather J., Milosevic, Jelena, Sykes, David B., Hsu, Peggy P., Vander Heiden, Matthew G., Vidoudez, Charles, Trauger, Sunia A., Haigis, Marcia C., Scadden, David T.
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; aspartate; bone marrow niche; cell metabolism; chemotherapy; glutamine; Medicin och hälsovetenskap; mouse models; patient-derived xenografts; pyrimidine synthesis; tumor microenvironment
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.07.009

Cancer relapse begins when malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the byproducts of the massive cell death in the surrounding region. In acute myeloid leukemia, complete remissions are common, but few are cured. We tracked leukemia cells in vivo, defined the moment of maximal response following chemotherapy, captured persisting cells, and conducted unbiased metabolomics, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine and glutathione generation, but not the mitochondrial tricarboxylic acid cycle. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual leukemia-initiating cells and improved survival in leukemia mouse models and patient-derived xenografts. We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploit a transient vulnerability and induce metabolic collapse in cancer cells to overcome chemoresistance. [Display omitted] •Untargeted metabolomics reveals the in vivo metabolic profile of AML cells•AML cells exhibit transient metabolic changes in response to chemotherapy•Glutamine or pyrimidine metabolism can be targeted to eliminate persisting cells•LepR+ stromal cells provide aspartate to support pyrimidine generation by AML cells Chemotherapy effectively induces remission in acute myeloid leukemia, yet in most patients, a few highly adaptable cells survive and cause relapse. van Gastel et al. show that residual leukemia cells exhibit transient metabolic adaptations enabling their survival. Timed targeting of these programs provokes a metabolic collapse and overcomes chemoresistance.